The long-term objectives of the proposed studies are to identify, characterize, and propagate suppressor T cells in vitro that are obtained from human allograft recipients, and utilize such suppressor T cells In adoptive transfer experiments in an attempt to promote long-term allograft tolerance in vivo. The specific alms of the project are to address the following questions: 1) Can functionally active T-suppressor cells from the peripheral blood of allograft recipients be induced by autologous alloreactive T cells and be propagated in vitro; 2) What biologic factors affect the induction and propagation of T-suppressor cells in vitro; 3) What are the functional characteristics of T-suppressor cells that are induced In vitro; 4) What T cell factors mediate suppression; 5) Do autologous T cells Induced in vitro under different conditions have similar functional characteristics; 6) Can autologous T cells or factors produced by such cells be used to promote in vivo allograft acceptance by adoptive transfer using primate models; 7) Can T-suppressor cells be induced in vivo by host-treatment with appropriate inducer cell populations? T-suppressor cells will be generated in vitro by co-culturing peripheral blood lymphocytes from kidney, liver, and heart transplant recipients with autologous alloreactive T cells derived from their allografts. The feasibility of inducing and propagating such suppressor cells from human transplant recipients has been substantiated in our preliminary Investigations. The studies proposed herein will provide a more detailed understanding of the functions and phenotypes of these cells and the circumstances under which they can be generated. Our ultimate goal is to use the results of the proposed in vitro studies as a guide in attempting in vivo adoptive transfer of T-suppressor cells or their soluble mediators in primate and eventually human allograft recipients. A rationale and precedent for this approach is provided by the use of T cell products (e.g., interleukins, interferons) and in vitro activated T cells (e.g., lymphokine activated-killers or LAK cells) in clinical trials to promote host-specific immunity against tumors. Our studies propose an analogous approach to provide specific host unresponsiveness to transplants. The ability to generate autologous in vitro activated T-suppressor cells post- transplant could potentially be applied in reversing allograft rejection or inducing tolerance, thus allowing the reduction or elimination of immunosuppressive drugs which provide the major cause of morbidity and mortality in transplant recipients.